The First Locally Acting Anti-Inflammatory Stem Cell-Based Therapy for Rheumatoid Arthritis Despite improved therapy; rheumatoid arthritis (RA) remains a significant unmet medical need. The long-term goal of this project is to advance the first stem cell-based product for anti-inflammatory therapy of RA. Many ongoing or completed clinical trials have established that mesenchymal stem cell (MSC)-based therapies are safe and effective in the treatment of human diseases. MSCs used in these therapies are derived from various adult human tissues, naturally home to inflamed sites, and help to repair these sites by establishing a local anti-inflammatory microenvironment. Extensive research has shown that MSCs from one human do not cause an immune response in another, nor is an immune response elicited in animals injected with human MSCs. As a result, many new and existing businesses are developing off-the-shelf allogeneic (non-self) MSC-based products for the treatment of a wide-ranging set of human diseases. However, one major drawback is that the current methods to prepare MSCs yield a mixed, poorly defined pool of cells that make the therapeutic out- comes inconsistent and difficult to predict. We have developed a new technology that renders MSC preparations more uniform by inducing them into a discrete anti-inflammatory phenotype (MSC2). Wibi+Works, LLC intends to market MSC2 as an off-the-shelf product for the targeted treatment of human inflammatory diseases. [Our central hypothesis for this study is that MSC2-based therapy is consistently safe and effective in the local anti-inflammatory treatment of rheumatoid arthritis. MSC2 are expected to home to inflamed sites and through their secretion of soluble factors and cell-cell contact with inflammatory cells to shit the affected tissue milieu toward homeostasis and repair. The overall goal of this Phase I study is to generate proof of principle data validating MSC2 as a consistently local anti-inflammatory therapy that safely improves disease outcomes in an established murine collagen induced arthritis model. Further, by specifically acting at the affected site many of the adverse effects seen with conventional systemic anti-inflammatory treatments will be avoided by this cell-based therapy. The aims we propose in pursuit of this goal are: 1. Determine the efficacy of MSC2 over conventional MSC treatment in murine collagen-induced arthritis (CIA), and 2. Determine the mechanisms behind decreased arthritis severity in MSC2-treated CIA mice.] In the follow-up Phase II study, it is expected that a clinical grade MSC2 product (wibi+cells) will be expanded, banked and tested for safety, efficacy, tumorigenicity, and toxicity in anticipation of filing withthe FDA to designate wibi+cells as an investigational new drug (IND) to test in pilot clinical trials o RA. This Phase I study represents the initial step for Wibi+Works, LLC in its goal of producing the first anti-inflammatory MSC2-based therapy of rheumatoid arthritis in the US and that stands alone as a local, not systemic, treatment with the potential to promote the repair of affected joints.